ReviewofMeningiomaHistopathologyWord格式文档下载.docx

ReviewofMeningiomaHistopathologyWord格式文档下载.docx

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AbstractandIntroduction

Abstract

Thehistologicalappearanceofameningiomaisanimportantpredictoroftumorbehaviorandisfrequentlyafactorindecisionsconcerningtherapy.TherelationshipbetweenhistologicalfeaturesandprognosisisformalizedingradingschemessuchasthosepublishedbytheWorldHealthOrganization（WHO）,mostrecentlyin2007.Althoughthelatesteditionisanimprovementoverpreviousgradingschemes,theWHOschemestillfailstofullyaddressavarietyofimportantissuesregardingtherelationshipbetweenmeningiomahistologicalcharacteristicsandbehavior.Inparticular,routinehistologicalexaminationfailstoidentifythesubsetofGradeItumorsthatbehaveaggressively.Becauseofthis,manyadditionalprognosticmarkersthatrequireimmunohistochemical,cytogenetic,ormoleculartechniquestoevaluateareunderinvestigation.Onlyone,immunohistochemistryfortheproliferationmarker,Ki67（MIB-1）,isusedroutinelyandithasonlylimitedutility.Itishopedthatanunderstandingofthegeneticchangesthatunderlietumorprogressionwillimprovehealthcareprofessionals'

abilitytopredictthebehaviorofmeningiomas.

Introduction

Meningiomasareneoplasmsderivedfromarachnoidal（meningothelial）cells.Theselesionscanoccurinpeopleofanyagebutcommonlypresentinmiddleage.Womenaremorelikelytodevelopameningioma,withafemale/maleratioofapproximately2:

1intracraniallyand10:

1inthespine.Mostmeningiomasarebenign（"

classic,"

GradeI）,well-circumscribed,slow-growing,andcurablebysurgerydependingonlocation.[18]

However,somemeningiomasareclinicallyaggressiveandcanleadtosignificantcomplicationsandevendeath.Many,butnotall,oftheseaggressivetumorsarehistologicalGradeII（atypical）orGradeIII（anaplasticormalignant）tumors.Asof2007,theformerwasreportedtoaccountforbetween4.7and7.2%ofmeningiomas,whereasthelattercomprised1.0to2.8%.[18,30]Theauthorsofsomestudieshavefoundalargerproportion,approximately20%oftheselesions,tohaveaggressivehistologicalfeatures.[32]Interestingly,thefemalepredominanceintheincidenceofmeningiomasdoesnotholdfortheseaggressivetumors.[32]

Twoofthemostimportantfactorsthatdeterminetheprognosisinpatientswithmeningiomasaretheextentoftheresectionandthetumor'

shistologicalgrade.Highergrademeningiomasaremorelikelynottoreceiveagross-totalresection,andevenwhentheydo,theremaystillberecurrence.[7,29]Asanexample,theauthorsofonestudyfoundthatwithin5yearsofresection,12%ofbenignmeningiomasrecurredcomparedwith41%ofGradeIItumors.[32]Onceatumorrecurs,itismorelikelytodosoagain,ultimatelyleadingtoalossoflocalcontrolandrarely,metastasis.[5,8,11]

OneofthemostcommonlyusedclassificationandgradingsystemsformeningiomaswassetforthbytheWHOin2000,andveryrecentlyupdatedin2007.[18,30]Thissystemsummarizesmuchofwhatisknownaboutthefeaturesseenonroutinehistologicalexaminationthatpredictaggressivebehaviorinmeningiomas.The2000versionrepresentedasignificantimprovementoverpreviousgradingschemesandislittlechangedinthe2007version.However,somelimitationsandpitfallsingradingmeningiomasremainandwillbeoutlinedhere.

Becausethelimitsofroutinehistologicalexaminationinpredictingtumorbehaviorhaveperhapsbeenreached,alargenumberofancillarytechniquesareunderevaluation,includingcytogeneticsandtheuseofimmunohistochemicalmarkers.Sofarmostofthesetechniquesremainintheliteratureandhavenotenteredtheroutineworkupforpatientswithmeningiomas.TwoexceptionsincludeimmunohistochemistryfortheproliferationmarkerKi67（MIB-1）andforPR.Neitherofthesemarkershasbeenincorporatedintothe2007WHOgradingschemeformeningiomas,althoughtheirsignificanceiscited.MeasurementofKi67byimmunohistochemistryfortheMIB-1antigenisnotuncommonlyusedasanadditionalwayofevaluatingameningioma'

spotentialforaggressivebehavior.TestingforthepresenceorabsenceofPRsisusedlessoftenbutisofspecialinterestbecausePRantagonistshavebeenusedclinicallytotrytocontrolthegrowthofmeningiomas.

Theissueofmalignantprogressioninmeningiomasatboththegeneticandhistologicallevelsisanareaofactiveresearch.Compellingevidenceforprogressionhasbeendiscoveredatthegeneticlevel,andthelistofgeneticalterationsassociatedwithdifferenttumorgradescontinuestoexpand.Acompletediscussionofthemoleculargeneticsofmeningiomasisbeyondthescopeofthispaper;

however,someofthemoresignificantfindingswillbementioned.

TheWHOClassificationandGradingofMeningiomas

Background:

The1993Version

Inthelate1990sanumberofpublishedgradingsystemsformeningiomaswereinuse.Thismadeitdifficulttocomparedatafromdifferentsources.Furthermore,thedifferentgradingsystemssufferedfromvariousweaknesses,includingvaguenessandsubjectivityofcriteria.[22]

OneofthesegradingsystemswastheWHOclassificationpublishedin1993.[17]Thereweretwocomponentstothisgradingsystem.ThefirstwasaschemebywhichcertainhistologicalfeatureswereassessedtodecideifmeningiomasweretheusualGradeItumorsoriftheywerehighergrade.GradeIImeningiomasweredefinedasthose"

inwhichseveralofthefollowingfeaturesareevident:

frequentmitoses,increasedcellularity,smallcellswithhighnucleus/cytoplasmratiosand/orprominentnucleoli,uninterruptedpatternlessorsheetlikegrowth,andfociofspontaneousorgeographicnecrosis."

Ananaplasticormalignant（GradeIII）meningiomaexhibited"

histologicalfeaturesoffrankmalignancyfarinexcessoftheabnormalitiesnotedinatypicalmeningiomas."

NeededModifications:

TheContributionoftheMayoClinicStudies

Theextremevaguenessandsubjectivityofthecriteriaforatypicalandanaplasticmeningiomasinthisschemeisclear.Howmanyis"

frequent"

?

Howmuchmoreis"

increased"

Exactlyhowmanyis"

several"

InvestigatorsattheMayoClinicpartiallyaddressedtheseproblemsbypublishingtwolargestudieswithtwomaingoals:

clarifyingthesignificanceofbraininvasionanddevelopingobjectivecriteriathatwouldallowreproduciblegradingofmeningiomas.Anumberoftheircriticalfindingswereadoptedinthe2000revisionoftheWHOclassificationofbraintumors.Themeningiomagradingschemerecentlypublishedinthe2007revisionisalmostidenticaltothatproposedbytheMayogroupbasedonthesetwostudies.

DefiningAtypicalMeningiomas

Thefirststudywasaretrospectiveanalysisof581patientswithprimarymeningiomas.[32]Init,theinvestigatorsexaminedthecorrelationbetweennumerousparameters,histologicalandotherwise,andprogression-freesurvival.Indefiningthegradingcriteria,theyincludedonlypatientswithgross-totalresections（463patients）.

Thepresenceofmitoticfiguresnumberingfourormoreper10hpfwerehighlypredictiveofrecurrenceandbecameoneofthecriteriaforatypicalmeningioma.Thesecond,independentcriteriontheresearchersfromtheMayoClinicusedwasthepresenceofatleastthreeofthefollowingfourparameters:

"

sheeting"

（Fig.1A）,prominentnucleoli（Fig.1B）,hypercellularity,andtheformationofsmallcells（Fig.1C）.Applyingtheproposedcriteria,81%oftheirmeningiomaswereclassicand15%atypical.Theremaining4%showedbraininvasionandweredealtwithseparately.The5-yearrecurrencerateswere12%forclassictumorsand41%foratypicaltumors.Atypicaltumorswereassociatedwithdecreasedoveralllengthofsurvival;

classicmeningiomaswerenot.

Figure1. 

（clickimagetozoom）

PhotomicrographsdemonstratingthreeofthehistologicalcriteriaforatypiaaccordingtotheMayoClinicgradingschemeformeningiomas.A）patternlessarchitectureor"

sheeting;

"

B）prominentnucleoli（arrowindicatesamitoticfigure）;

andC）formationofsmallcells.H&

E,originalmagnification×

100（A）,×

400（BandC）.

PreliminaryFindingsConcerningBrainInvasion

Mostmeningiomashavea"

pushing"

borderwiththebrainanddonotbreachthepia.Ontheotherhand,somemeningiomasexhibitbraininvasioncharacterizedbyanirregularborderbetweenthetumorandbrainwithoutinterveningleptomeninges.Thebrainshowsaglioticresponseandthereisoftenentrapmentofislandsofbrainparenchymawithinthetumor（Fig.2）.AtthetimeoftheMayoClinicstudies,braininvasionwasoftenequatedwithmalignancy,irrespectiveoftheotherhistopathologicalfeaturesofthetumor.[32]

Figure2. 

Immunohistochemicalstainingforglialfibrillaryacidicproteindemonstratingmeningiomawithbraininvasion.Thebrainparenchymastainspositive（brown）forthisprotein,andthemeningiomastainsnegative（purple）,highlightingtheextensiveinterminglingofthetwotissues.Streptavidin–biotin,magnification×

200.

InthefirstMayoClinicstudy,braininvasionwasapowerfulpredictorofshorterrecurrence-freesurvival.[32]Ofbraininvasivetumorsintheirstudy,43%hadclassichistologicalcharacteristicsand57%wereatypical.Therecurrencerateofinvasivetumors,whetherotherwisebenignoratypical,wasnotstatisticallydifferentfromthatofnoninvasiveatypicaltumors.Howeve